OTX-015
OTX-015 is a potent inhibitor of BRD2, BRD3, and BRD4 with IC50 values range from 92 to 112 nM [1].
BRD2, BRD3, and BRD4 belong to BET bromodomain family and play an important role in regulating transcription. BRDs regulate several oncogenes transcription in a variety of cancers and thus have emerged as a promising target [2].
OTX-015 is a selective BRD2, BRD3, and BRD4 inhibitor and inhibits the binding of BRD2, BRD3, and BRD4 to AcH4. Using TR-FRET method and CHO cell lysate harboring BRD2, BRD3, and BRD4 to research the effect of OTX-015, result showed that OTX-015 inhibited BET family binding to AcH4 in a dose-dependent manner and the EC50 values range from 10 to 19 nM. When tested with human tumor cell lines, incubation with OTX-015 for 72 hours inhibited cell proliferation with GI 50 values ranged from 60 to 200 nM [1]. In ALKpos ALCL cell lines, treatment of OTX-015 for 24 h arrested cell proliferation in G1 phase which was more pronounced at 48 h and 72 h, and tested with SUPM2/TS and JB-6 cell lines OTX-015 showed ability to increase cell death rate [3].
In BLAB/c-nu/nu mice model with established Ty82 BRD-NUT midline carcinoma xenografts, oral administration of OTX-015 markedly inhibited tumor growth and reduced tumor volume [1].
References:
[1]. J. Kay Noel, Kazunori Iwata, Shinsuke Ooike, et al. Development of the BET bromodomain inhibitor OTX015 [J]. Mol Cancer Ther November 2013 12; C244.
[2]. Fu LL, Tian M, Li X, et al. Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery [J]. Oncotarget. 2015 Mar 20;6(8):5501-5516.
[3]. Michela Boi, Maria Todaro, Valentina Vurchio, et al. OTX015, a bromodomain and extraterminal inhibitor, represents a novel agent for ALK positive anaplastic large cell lymphoma [J]. Mol Cancer Ther November 2013 12; A219.
- 1. Te Zhang, Xuming Song, et al. "Aberrant super-enhancer landscape reveals core transcriptional regulatory circuitry in lung adenocarcinoma." Oncogenesis. 2020 Oct 17;9(10):92. PMID:33070167
- 2. Zhao M, De Crignis E, et al. "T cell toxicity of HIV latency reversing agents." Pharmacol Res. 2018 Oct 23. pii: S1043-6618(18)30970-8. PMID:30366100
- 3. Qian G, Yao W, et al. "Co-inhibition of BET and proteasome enhances ER stress and Bim-dependent apoptosis with augmented cancer therapeutic efficacy." Cancer Lett. 2018 Oct 28;435:44-54. PMID:30059709
- 4. Abner E, Stoszko M, et al. "A new quinoline BRD4 inhibitor targets a distinct latent HIV-1 reservoir for re-activation from other 'shock' drugs." J Virol. 2018 Jan 17. pii: JVI.02056-17. PMID:29343578
| Storage | Store at -20°C |
| M.Wt | 491.99 |
| Cas No. | 202590-98-5 |
| Formula | C25H22ClN5O2S |
| Synonyms | OTX 015;OTX015 |
| Solubility | ≥24.6 mg/mL in DMSO; insoluble in H2O; ≥106 mg/mL in EtOH with gentle warming |
| SDF | Download SDF |
| Canonical SMILES | CC1=C(SC2=C1C(=NC(C3=NN=C(N32)C)CC(=O)NC4=CC=C(C=C4)O)C5=CC=C(C=C5)Cl)C |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Kinase experiment [1]: | |
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Binding assays |
To assess binding of OTX015 to BRD2, BRD3, and BRD4, BRD-expressing CHO cell lysate (from CHO cells transfected with expression plasmids for Flag-tagged BRD2, BRD3, or BRD4 or vector alone), europium-conjugated anti-Flag antibody, XL-665-conjugated streptavidin, and biotinylated OTX015 were incubated at room temperature for 0.2 to 2h. Fluorescence was measured by TR-FRET using an EnVision 2103 Multilabel Reader and EC50 for binding was calculated by nonlinear regression using PRISM version 5.02. Using a similar system, the effect of OTX015 on binding of BRD2, BRD3, and BRD4 to acetylated histone H4 (AcH4) was evaluated by incubating biotin-conjugated -AcH4, BRD-expressing CHO cell lysate, europium-conjugated anti-Flag antibody, and XL-665-conjugated streptavidin. Fluorescence was measured by TR-FRET using an EnVision 2103 Multilabel Reader and percent binding was calculated by defining the value of the sample without biotin conjugate dAcH4 as 0% and the sample without OTX015 as 100%. The IC50 value was calculated by nonlinear regression using PRISM version 5.02. |
| Cell experiment [1]: | |
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Cell lines |
Human tumor cells |
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Preparation method |
Soluble in DMSO > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reaction Conditions |
72 h. |
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Applications |
OTX-015 inhibits the growth of a variety of human cancer cell lines. OTX-015 exhibits growth inhibition with GI50 values of 60-200 nM for most hematologic malignancies tested. |
| Animal experiment [1]: | |
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Animal models |
BLAB/c-nu/nu mice bearing established Ty82 BRD-NUT midline carcinoma xenografts. |
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Dosage form |
0, 10, 30 or 100 mg/kg qd or 10 mg/kg bid; 14 days; oral gavage. |
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Applications |
OTX-015 significantly inhibits tumor growth and exhibits TGI by 79% and 61% at 100 mg/kg qd and 10 mg/kg bid. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. J. Kay Noel, Kazunori Iwata, Shinsuke Ooike, et al. Development of the BET bromodomain inhibitor OTX015 [J]. Mol Cancer Ther, 2013, 12(11 Suppl): C244. |
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| Description | OTX-015 is an orally bioavailable and small molecule inhibitor of bromodomain and extra terminal domain (BET) family proteins with EC50 values of 10-19 nM for BRD2, BRD3, and BRD4. | |||||
| Targets | BRD2 | BRD3 | BRD4 | |||
| IC50 | ||||||
Quality Control & MSDS
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